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. 2012 Jul;20(7):734-41.
doi: 10.1038/ejhg.2012.7. Epub 2012 Feb 22.

Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients

Silvia Russo  1 , Maura Masciadri, Cristina Gervasini, Jacopo Azzollini, Anna Cereda, Giuseppe Zampino, Oskar Haas, Gioacchino Scarano, Maja Di Rocco, Palma Finelli, Romano Tenconi, Angelo Selicorni, Lidia Larizza
Affiliations

Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients

Silvia Russo et al. Eur J Hum Genet. 2012 Jul.

Abstract

Cornelia de Lange syndrome (CdLS) is a rare multisystemic congenital anomaly disorder that is characterised by intellectual disability and growth retardation, congenital heart defects, intestinal anomalies, facial dysmorphism (including synophyris and high arched eyebrows) and limb reduction defects. Mutations in three cohesin-associated genes encoding a key regulator (NIPBL, chr 5p13.2) and one structural component of the cohesin ring (SMC1A, chr Xp11) occur in about 65% of CdLS patients. NIPBL is the major causative gene, and accounts for 40-60% of CdLS patients as shown by a number of mutational screening studies that indicate a wide mutational repertoire of mainly small deletions and point mutations. Only a few data are available concerning the occurrence of large NIPBL rearrangements or intragenic deletions or duplications involving whole exons. We used multiplex ligation-dependent probe amplification (MLPA) to study 132 CdLS patients negative to the standard mutation NIPBL test out of a cohort of 200 CdLS patients. A total of 7 out of 132 patients were found to carry NIPBL alterations, including two large gene deletions extending beyond the gene, four intragenic multi- or single-exon deletions and one single-exon duplication. These findings show that MLPA leads to a 5.3% increase in the detection of mutations when used in addition to the standard NIPBL scan, and contributes per se to the molecular diagnosis of 3.5% (7/200) of clinically diagnosed CdLS patients. It is recommended that MLPA be included in the CdLS diagnostic flow chart.

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Figures

Figure 1
Figure 1
Overall picture of MLPA-detected large deletions/duplications involving the NIPBL gene. (a) Schematic illustration of the NIPBL gene: the black bars mark the genomic deletions in patients 1 and 7 and the skipped exons in patients 2, 3, 4, and 5; the findings relating to two previously described patients in the literature are also included. The dashed bars indicate the duplications of patient 6 and the patient reported by Vrouwe; the large genomic duplications reported by Yan et al are not included because they are out of scale. The genomic boundaries of the rearrangements of pts 1 and 7 and cDNA boundaries of pts 2, 3, and 4 are indicated at the ends of each bar. (b) Schematic illustration of the NIPBL protein with its putative domains and motifs: the asterisks indicate the localisation of the predicted deleted amino-acid residues (patients 4 and 5) and the protein truncation start site (patient 3).
Figure 2
Figure 2
The clinical and genomic data of patient 1, suggesting a contiguous gene syndrome involving NIPBL. (a) Severe limb reduction and typical CdLS facial dysmorphism. (b) In the MLPA histograms, the red rectangles and arrows indicate the halved columns of the deleted exons: exon 1–10. (c) Ideogram of chromosome 5 and genomic details of the deleted 2 Mb region at 5p13.2 (red bar): the BAC clones used for the FISH characterisation are represented by horizontal bars and the NIPBL gene is schematically shown with all of its exons. MLPA indicated that the first 10 exons of NIPBL are deleted. The metaphase panels showed that RP11-165J8 gave only one signal, RP11-1123B20 and RP11-620F21 gave one normal and one faint signal, and RP11-8C23 gave two signals mapping outside the deleted region.
Figure 3
Figure 3
Vertical panels showing (from top to bottom) MLPA analysis (a, f and j), RT-PCR (c, g and k), and the sequencing of the wild type (d and h) and aberrant (e, i and m) transcripts of patients 2, 3, and 4. In the MLPA histograms, the red arrows indicate the halved columns of the deleted exons: exon 2 in patient 2, exon 3 in patient 3, and exons 25, 26, and 27 in patient 4. All of the RT-PCRs revealed a wild type and a lower band corresponding to the deleted fragment, whose sequence indicates the exact splice-junction. The pictures of patients 2 (b) and 4 (l) show the typical facial dysmorphism of CdL syndrome.
Figure 4
Figure 4
Clinical and genomic data of patient 7. (a) MLPA histograms: NIPBL exons arrowed in red (2–47) show reduced height in comparison with the control probes (0.7 vs 1.4). (b) a-CGH profile focussing on a 1.4 Mb window within the 5p13.2 interval containing the NIPBL deletion; the scatter plot shows a deletion in 5p13.2 (the shift is marked by green dots under 0). Each dot represents a single probe.
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